The overall goal of the Yale Interdisciplinary Center for Polycystic Kidney Disease Research is to elucidate the mechanisms by which defects in the polycystin genes result in autosomal dominant polycystic kidney disease (ADPKD) and to understand the factors that modify the expression of the disease phenotype. Central to achieving these goals will be a focus on state- of-the-art transgenic and ES cell technology to support the development of authentic mouse models of human ADPKD. Recent work by the Director has developed a spectrum of mouse models with inactivation of Pkd2 gene expression resulting in PKD which resembles the human disease. These studies will be extended to generate a conditional Pkd2 gene inactivation model in which there will be spatial and temporal control of gene inactivation. In addition, cell lines that are genetically identical except for the presence or absence of functional polycystin-2 will be generated from specific adult nephron segments. Taking advantage of the availability of these novel mouse models and cell lines, projects will explore the physiological, cell biological, and developmental mechanisms leading to the disease phenotype. Mouse models will be used to study the pathogenesis of cyst formation in adult mice (Project 1), the role of Pkd2 in kidney development (Project 2), and the role of polycystin-2 in converting renal tubular cells to the secretory transport phenotype (Project 4). Cell lines with genetically altered polycystin-2 expression will be used for studies of intracellular trafficking and protein interactions (Project 3), and a characterization of its ion channel proteins (Project 5). To successfully complete this comprehensive analysis of the role of polycystins in renal pathobiology, the Center will involve a team of principal investigators representing a broad array of scientific disciplines including genetics (Somlo), developmental biology (Igarashi), cell biology (Caplan), renal physiology (Aronson), and ion channel electrophysiology (Ehrlich). The projects will be supported by the availability of core facilities for the generation and maintenance of mutual mice, and for the use of imaging techniques to analyze PKD at the cellular and molecular level.